A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development.
A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development.
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DOI：
10.1073/pnas.2022546118
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发表时间：
2021-12-07
影响因子：
11.1
通讯作者：
Sweet RA
中科院分区：
文献类型：
--
作者：
Grubisha MJ;Sun T;Eisenman L;Erickson SL;Chou S;Helmer CD;Trudgen MT;Ding Y;Homanics GE;Penzes P;Wills ZP;Sweet RA
树突是神经元上的长分支过程，包含称为棘的小过程，棘是与其他神经元连接的部位，建立皮层电路。树突长期以来被认为是稳定的结构，在青春期之前快速生长，然后在成年期保持大小。然而，精神分裂症的特征是在青春期皮质灰质体积的加速减少和临床症状的发作，死亡后检查时树突长度减少。我们表明，树突保留的能力，回归和轻度遗传脆弱性的回归途径导致发病的结构障碍，在以前形成的树突在整个青春期。这表明，针对特定的回归途径可能会导致精神分裂症的新疗法。正常情况下，树突的大小在青春期之前建立，然后由于生长和收缩途径之间的稳态平衡而保持相对恒定到成年。然而，精神分裂症的特点是大脑皮质灰质体积的加速减少和青春期临床症状的发作，在死后的多个皮质区域中鉴定出第3层锥体神经元树突长度、复杂性和棘密度的减少。Nogo受体1（NGR 1）激活GTdR RhoA是限制大脑皮层中树突生长的主要途径。我们表明，NGR 1途径是由OMG p刺激，并需要Rho鸟嘌呤核苷酸交换因子Kalirin-9（KAL 9）。使用遗传编码的RhoA传感器，我们证明了在精神分裂症队列中发现的Kalrn，KAL-PT中天然存在的错义突变，与野生型KAL相比，赋予神经元树突中增强的RhoA激活。在内源性位点含有这种错义突变的小鼠中，初级听觉皮层中的第3层锥体神经元的树突长度和复杂性有一个明显的减少。每单位长度树突的棘密度不受影响。这些结构缺陷的早期成年小鼠表现出受损的检测短间隙持续时间。这些发现提供了一种神经精神疾病模型，捕捉了轻度遗传脆弱性如何与正常发育过程相互作用，使得病理仅在青春期左右出现。遗传易感性和正常的青少年发育之间的相互作用，这两者都具有固有的个体差异，可能有助于异质性在人类神经精神疾病的表型。
Dendrites are long branching processes on neurons that contain small processes called spines that are the site of connections with other neurons, establishing cortical circuitry. Dendrites have long been considered stable structures, with rapid growth prior to adolescence followed by maintenance of size into adulthood. However, schizophrenia is characterized by accelerated reductions of cortical gray matter volume and onset of clinical symptoms during adolescence, with reductions in dendritic length present when examined after death. We show that dendrites retain the capacity for regression and that a mild genetic vulnerability in a regression pathway leads to onset of structural impairments in previously formed dendrites across adolescence. This suggests that targeting specific regression pathways could potentially lead to new therapeutics for schizophrenia. Normally, dendritic size is established prior to adolescence and then remains relatively constant into adulthood due to a homeostatic balance between growth and retraction pathways. However, schizophrenia is characterized by accelerated reductions of cerebral cortex gray matter volume and onset of clinical symptoms during adolescence, with reductions in layer 3 pyramidal neuron dendritic length, complexity, and spine density identified in multiple cortical regions postmortem. Nogo receptor 1 (NGR1) activation of the GTPase RhoA is a major pathway restricting dendritic growth in the cerebral cortex. We show that the NGR1 pathway is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor Kalirin-9 (KAL9). Using a genetically encoded RhoA sensor, we demonstrate that a naturally occurring missense mutation in Kalrn, KAL-PT, that was identified in a schizophrenia cohort, confers enhanced RhoA activitation in neuronal dendrites compared to wild-type KAL. In mice containing this missense mutation at the endogenous locus, there is an adolescent-onset reduction in dendritic length and complexity of layer 3 pyramidal neurons in the primary auditory cortex. Spine density per unit length of dendrite is unaffected. Early adult mice with these structural deficits exhibited impaired detection of short gap durations. These findings provide a neuropsychiatric model of disease capturing how a mild genetic vulnerability may interact with normal developmental processes such that pathology only emerges around adolescence. This interplay between genetic susceptibility and normal adolescent development, both of which possess inherent individual variability, may contribute to heterogeneity seen in phenotypes in human neuropsychiatric disease.
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影响因子：
25
作者：
Chow, David K.;Groszer, Matthias;Pribadi, Mochtar;Machniki, Michal;Carmichael, S. Thomas;Liu, Xin;Trachtenberg, Joshua T.
通讯作者：
Trachtenberg, Joshua T.
影响因子：
1.9
作者：
Guo, Dayong;Li, Xiaojing;Wang, Hongyu
通讯作者：
Wang, Hongyu
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
5.3
作者：
Green, Michael F.
通讯作者：
Green, Michael F.
自闭症谱系障碍（ASD）、精神分裂症和双相情感障碍中全转录组异构体水平失调
影响因子：
56.9
作者：
Gandal, Michael J.;Zhang, Pan;Geschwind, Daniel H.
通讯作者：
Geschwind, Daniel H.